Phosphonates

ABSTRACT

PREPARATION OF A,B-UNSATURATED CARBOCYCLIC KETONES BY REACTING AN ENOL LACTONE WITH A CARBANION GENERATED BY TREATMENT OF A METHYLPHOSPHONATE OR A MONO-SUBSTITUTED METHYLPHOSPHONATE WITH BASE.

3,773,789 PHOSPHONATES John H. Fried, Palo Alto, Calif., assignor toSyntex Corporation, Panama, Panama No Drawing. Original application Dec.4, 1967, Ser. No. 687,502, now Patent No. 3,639,428, dated Feb. 1, 1972.Divided and this application Mar. 18, 1971, Ser.

Int. Cl. C07d 13/04 US. Cl. 260-3403 4 Claims ABSTRACT OF THE DISCLOSUREPreparation of c p-unsaturated carbocyclic ketones by reacting an enollactone with a carbanion generated by treatment of a methylphosphonateor a mono-substituted methylphosphonate with base.

This is a division of application Ser. No. 687,502 filed Dec. 4, 1967,now US. Pat. 3,639,428 issued Feb. 1, 1972.

The present invention relates to the production of unsaturatedcarbocyclic ketones.

More particularly, this invention relates to a novel process which hasgeneral utility [for the conversion of enol lactones into cp-unsaturated carbocyclic ketones.

The expression enol lactone, as used herein, refers to an unsaturatedlactone having a, 3-ethylenic unsatura tion in respect to theheterocyclic oxygen atom. The exp'ression mp-unsaturated carbocyclicketone, as used herein, refers to a carbocyclic ketone havinga,fl-ethylenic unsaturation in respect to the keto group.

Prior to the present invention, enol lactones were converted intonap-unsaturated carbocyclic ketones by a twostep process which involvedreacting the enol lactone with about one equivalent of a Grignardreagent, for example, methyl-magnesium chloride, to open the lactonering and thereafter the thus-obtained diketonic intermediate product wascyclized by treatment with acid or alkali to obtain the carbocyclicketone. See, for example, US. Pats. 3,057 907 and 3,321,489 and FrenchPat. 1,359,675. In addition to the disadvantage that the conversion ofenol lactones into carbocyclic ketones requires at least two steps,prior methods are often difficult to control, unsuitable for 5-memberedring systems, and of very narrow utility in that the a ti-unsaturatedcarbocyclic ketones obtainable are very limited.

A primary object of the present invention, therefore, is to provide aprocess for the production of p s-unsaturated carbocyclic ketones fromenol lactones which overcomes the aforementined disadvantages. Anotherobject of the present invention is to provide a process for theproduction of a,fl-unsaturated carbocyclic ketones which is economicaland simple to operate but yet of great flexibility or adaptability inrespect to the type of c punsaturated carbocyclic ketone that can beproduced. Another object of this invention is to provide a single-stepprocess for the production of a,B-unsaturated carbocyclic ketones. Stillnother object of the present invention is to provide a process for theproduction of a,;8-unsaturated carbocyclic ketones which is useful inthe total synthesis of steroids and to novel intermediates therefor.Other objects, advantages and meritorious features of the presentinvention will become apparent as the invention is described in moredetail hereinafter.

In accordance with the foregoing objects of the present invention, therehas been discovered a very versatile process for the production ofnap-unsaturated carbocyclic ketones which comprises reacting, undersubstantially anhydrous conditions in an organic solvent inert to thereaction, an enol lactone with a carbanion generated by the UnitedStates Patent 0 "ice reaction of base with a phosphonate selected fromthe group consisting of methylphosphonates and mono-substitutedmethylphosphonates.

The process of the present invention is applicable to the conversion ofenol lactones into 0:,fi-111'1S21tll1'3t6d carbocyclic ketones ingeneral. The enol lactone can be either a monocyclic enol lactone or apolycyclic compound such as bicyclic, tricyclic and tetracyclic enollactones depending upon the a,fi-unsaturated carbocyclic ketone desiredto be obtained. The process of the present invention is particularlysuitable for enol lactone starting materials wherein the heterocyclicring thereof contains at least 5 members and mono-ethylenicunsaturation. The enol lactones which can be converted intoa,[3-unsaturated carbocyclic ketones by the process of this inventionare too numerous to list. Exemplary of the monocyclic and polycyclicenol lactones which can be used in the process of the present inventionare a-angelica lactone, A -valeryl lactone, isocoumarin,3-methyl-6,8-dimethoxyisocoumarin, 3-phenylisocoumarin, 3-benzoyl 7,8dimethoxyisocoumarin, 3- chloroisocoumarin, benzal phthalide,5,6,7-trimethoxyisocoumarin, fi-lactone of IB-hydroxy-ZB-methyl 2oz (2'-carboxyethyl)-3-hydroxycyclopent 3 ene, 5-lactone of lfi-hydroxy-4-(2-carboxyethyl) -5-hydroxy 7a,? methyl- 3aa,45,7,7a-tetrahydroidane,4-oxa-17fl acetoxyandrost- 5-en-3-one, 3-ethoxy-17-oxa-D-homoestra 1,3,5(10), 15- tetraen-17-one, 4-oxa-cholest-5-en 3 one,17,20;20,2lbismethylenedioxy-4-oxa-1lfi-hydroxypregn 5 en 3- one, and3-methoxy-l6-oxaestra-1,3,5 (l0),8,l4 pentaen- 17-one.

The phosphonates which are useful in the production of a,B-unsaturatedcarbocyclic ketones in accordance with the process of the presentinvention are the methylphosphonates and mono substitutedmethylphosphonates. Methylphosphonates and mono-substitutedmethylphosphonates useful in the present invention are illustrated bythe following formulas A and B, respectively:

wherein R is selected from the group consisting of substituted andunsubstituted, saturated and unsaturated, aliphatic, carbocyclic andcarbocyclic-aliphatic radicals and R is selected from the groupconsisting of substituted and unsubstituted, saturated and unsaturated,aliphatic, carbocyclic and carbocyclic-aliphatic radicals.

Phosphonates of Formulas A and B above can be prepared, for example, bythe reaction of a di-substituted phosphite (C) with an organic halide orsulfonate of the Formulas D and B, respectively, in the presence of abase, e.g. sodium hydride,

0 H-P (O R) 1 CHs'X RJ-CHr-X (C) In the above formulas, R and R are asdefined above and X is chloro or bromo, or OSO R wherein R is alkyl oraryl. The formation of the phosphonates can be carried out in inertsolvents such as-ether, tetrahydrofuran, monoglyme, diglyme, or dioxaneand preferably in an oxygen-free atmosphere. The method of preparing thephosphonates is not part of the present invention. A suitable procedurefor the formation of methylphosphonates and mono-substitutedmethylphosphonates useful in the present invention is to react adi-substituted phosphite of Formula C with an organic halide orsulfonate of Formulas D and E in an inert solvent in the presence ofabout one equivalent of a base such as sodium hydride under an inertatmosphere at a temperature of about -10 C. to about room temperature.Other methods are described in, for example, US. Pat. 2,754,319.

When the methylphosphonates and mono-substituted methylphosphonateswhich can be employed in the process of the present invention are toonumerous to list here, they can be exemplified by the following:

dimethyl methylphosphonate dimethyl ethylphosphonate diethylbenzylphosphonate diethyl methylphosphonate dicyclohexylmethylphosphonate diphenyl methylphosphonate di-(n-butyl)methylphosphonate dibenzyl methylphosphonate diethyl methylphosphonatediethyl 4,4-dimethoxybutylphophonate diethyl4,4-ethylenedioxypentylphosphonate dimethyl4,4-dimethoxy-3-methylbut-2-enylphosphonate diethyl4-chloropent-3-enylphosphonate diethyl4-(tetrahydropyran-2-yloxy)pentylphosphonate diethyl4,4-ethylenedioxy-3methylpentylphosphonate di(methoxyethyl)methylphosphonate di(2-ethylhexyl) methylphosphonate di(n-octyl)ethylphosphonate di(ethoxyethyl) methylphosphonate In the practice ofthe process of the present invention, a phosphonate of Formula A or B isreacted with a base to generate the corresponding carbanion of theFormulas A and B, respectively:

o EHr-i R):

Because of the general instability of the phosphonate carbanion, it isnecessary that the reaction between the phosphonate and base be carriedout at low temperatures of the order of about -150 C. to about -20 C.,preferably about 100 C. to about -40 C. After formation of the carbanionis complete, the low temperature of the reaction mixture is maintainedduring the addition of the enol lactone and thereafter the cooling meansremoved or otherwise raising the reaction temperature to about roomtemperature. Suitable bases for generating the carbanion include organoalkali metal compounds such as n-butyl lithium, phenyl lithium, methylsodium, sodium acetylide, methyl potassium, methyl lithium, tolyllithium, methyl potassium, lithium pyridide, and the like; alkali metalhydrides such as sodium hydride, potassium hydride or lithium hydride;alkali metal amides such as sodamide, and the like.

In practicing the conversion of an enol lactone into the corresponding cp-unsaturated carbocyclic ketone in accordance with the process of thepresent invention, the reaction is carried out using about equal molaramounts of the phosphonate, base and enol lactone. More than one molarequivalent of the phosphonate and base can be used but it is generallydisadvantageous to do so because the excess reagent may react furtherwith the carbonyl group of the desired carbocyclic ketone. Thus, it ispreferred to use about one molar equivalent of the phosphonate and baseor a modest excess of each such as up to about 1.2 molar equivalents.Any organic solvent can be used for the reaction medium so long as it isinert to the reaction and liquid at the reaction temperature being used.Suitable organic solvents include ether, tetrahydrofuran, dioxane,monoglyme, diglyme, and the like. The reaction between the carbanion andenol lactone generally goes to completion in from about 0.5 hour toabout 48 hours depending upon such factors as temperature and therelative reactivity of the carbanion and the enol lactone. The reactiontemperature can vary from about 150 C. to about room temperautre,preferably about 100 C. to about room temperature depending upon suchfactors as the stability of the carbanion, the relative reactivity ofcarbanion and enol lactone being reacted and the time in which it isdesired to complete the reaction After formation of the carbanion iscomplete and the enol lactone has been introduced, the reaction mixturecan be permitted to rise to about room temperature in order to completethe reaction in a shorter period of time. Depending upon the stabilityof the particular carbanion being used, the reaction mixture can beheated above room temperature, for example reflux temperature, if stillshorter reaction times are desired. However, because of the generalinstability of the carbanion, the reaction between the phosphonate andbase must be carried. out at low temperatures of the order of about C.to -20 C. For optimum results, it is important that the reaction beconducted under as near anhydrous conditions as possible and preferablyunder an inert oxygen-free atmosphere such as nitrogen, argon, and thelike. While the concentration of the enol lactone and carbanion does notappear to be critical, it is preferred to operate at low concentrationsof the order of about two to about twenty-five percent by weight of thereaction medium. The foregoing reaction conditions are largely dependentupon the particular phosphonate, base and enol lactone employed and arepresented as a guide. Provided with the foregoing and the exampleshereinafter, the most advantageous or optimum conditions and proportionsof the enol lactone, phosphonate and base for a particulara,,8-unsaturated carbocyclic ketone are easily determinable by one ofordinary skill in the art using routine experimentation.

In the case of enol lactone starting materials having other carbonylgroups present, e.g. an isolated keto group, it is preferable tointroduce a protecting group prior to the reaction. In general, thephosphonate anions tend to react faster with the enol lactone.

The novel process of the present invention is particularly useful forthe production of carbocyclic ketones suitable for the synthesis ofsteroids.

The term lower alkyl, as used herein, refers to an alkyl groupcontaining from 1 to 6 carbon atoms. The term carboxylic acyl group, asused herein, refers to an acyl group containing up to about 12 carbonsderived from substituted or unsubstituted carboxylic acids. Typical acylgroups include acetyl, trifruoroacetyl, trichloroacetyl, propionyl,butyryl, diethylaceryl, =benzoyl, cyclopentylpropionyl, adamatoyl,trimethylacetyl, phenylacetyl, undecenoyl, and the like.

The following examples are provided to illustrate the present invention.Unless otherwise stated, temperature is centigrade and proportions areparts by weight.

EXAMPLE 1 0 Ac Rt 0 In the above formulas, R is as defined above, R ismethyl, ethyl or propyl and Ac is hydrogen or a carboxylic acyl group.

To a solution of 1 g. of dimethyl methylphosphonate in 30 m1. of drytetrahydrofuran under nitrogen and cooled to 78", there is added oneequivalent of n-butyl lithium in hexane with stirring. After about 10minutes at -78, one equivalent of the tricyclic enol lactone (I) (R ismethyl; Ac is benzoyl) in 35 ml. of dry tetrahydrofuran is added. Thereaction mixture is allowed to rise to room temperature and stand forabout two hours. The reaction mixture is diluted with water andextracted with ether. The ether extracts are combined, washed withwater, dried and evaporated under reduced pressure to give thetricarbocyclic ketone (III) (R is methyl; Ac

is benzoyl) which can be further purified by chromatography, if desired.

The tricarbocyclic ketone (III) can be used to prepare therapeuticallyuseful l9-nor or A -steroids using the procedure of, for example, U.S.Pat. 3,150,152.

The tricyclic enol lactone of Formula '1 can be obtained according tothe procedure of French Pat. 1,359,- 675 (1964) or Velluz et al.,Tetrahedron, Suppl. 8, Part II, pp. 495-505 (1966) and references citedtherein.

The process of Example 1 is repeated with the exception of usingdimethyl ethylphosphonate in place of dimethyl methylphosphonate andthere is obtained the a,fl-unsaturated tricarbocyclic ketone of FormulaIV (R is methyl; Ac is benzoyl).

0 Ac RI EXAMPLE 2 To a solution of 4 g. diethyl4,4-ethylenedioxypentylphosphonate (V) (R is ethyl) in 50 ml. of drymonoglyme under nitrogen and cooled to about --80, there is added oneequivalent of n-butyl lithium in hexane with stirring. After about fiveminutes at 80, one equivalent of the tricyclic enol lactone (I) (R ismethyl; Ac is benzoyl) in 75 ml. of dry monoglyme is added and thereaction mixture allowed to rise to room temperature. The reactionmixture is allowed to stand for about 2.5 hours and then diluted withwater. The mixture is extracted with ether and the ether extractscombined, washed, dried and evaporated under reduced pressure to givethe tricarbocyclic ketone (VI) (R is methyl; Ac is benzoyl) which can befurther purified by chromatography on alumina.

{l on, Ha z)r o C i l: 1

0 o/ cm W The a,B-unsaturated tricarbocyclic ketone of Formula VI is anexcellent intermediate for the preparation of 19-nor steroids using theprocedure of, for example, French Pats. 1,369,964 (1964); 1,432,570(1964); 1,452,- 898 (1965) or Velluz et al., ibid.

The mono-substituted methylphosphonate (V) can be prepared using thefollowing procedure.

To a solution of 5. g. of pure sodium hydride in 200 ml. of drytetrahydrofuran under nitrogen, there is added one equivalent of drydiethyl phosphite. The mixture is cooled in an ice-bath andstirred at 0for 1.5 hours. One equivalent of the ethylene ketal of1-bromOpentan-4-one in 60 ml. of dry tetrahydrofuran is added and themix- 'ture stirred for 15 minutes at 0 and allowed to stand 16 hours atroom temperature. The mixture is then heated under reflux for threehours, cooled and filtered. The filtrate is concentrated under reducedpressure and the concentrate taken up in ether. This mixture is shakenwith saturated aqueous sodium chloride and then separated. The organiclayer is separated and concentrated under reduced pressure to givediethyl 4,4-ethylenedioxypentylphosphonate (V) (R is ethyl) which ispurified by distillation in vacuo (B.P. 115 at 0.05 mm.).

By using other phosphites, e.g. dimethyl phosphite, dibenzyl phosphiteor diphenyl phosphite, in place of diethyl phosphite in the aboveprocedure, the corresponding di-substituted phosphonates are obtained.

EXAMPLE 3 0A0 0A0 R4 4 II) (VIII) To a suspension of 2 g. of dimethylmethylphosphonate in 50 ml. of dry tetrahydrofuran at -78 undernitrogen, there is added one equivalent of n-butyl lithium in hexanewith stirring. After about five minutes, there is added one equivalentof bicyclic enol lactone (VII) (R is methyl; Ac is benzoyl) in 50 ml. ofdry tetrahydrofuran while maintaining the temperature at about -78. Thereaction mixture is allowed to warm to room temperature and to stand atroom temperature for three hours. The reaction mixture is diluted withwater and then extracted with ether. The ether extracts are combined,washed, dried and evaporated under reduced pressure to give thebicarbocyclic ketone (VHI) (R is methyl; Ac is benzoyl) which can befurther purified by chromatography or fractional distillation.

The c p-unsaturated bicarbocyclic ketone of Formula VIII is a valuableintermediate for the synthesis of steroids using the method of, forexample, Whitehurst et al., U.S. Pat. 3,317,566.

The bicyclic enol lactone of Formula VII can be prepared using thefollowing procedure.

A mixture of 0.3 ml. of 2-methylcyclopentane-1,3- dione, 0.33 ml. ofmethylacrylate and 0.1 g. of potassium tbutoxide in 200 ml. of t-butanolis allowed to stand at about 20 C. for 72 hours. The reaction mixture iswashed with water, dilute sodium hydroxide and then water to neutral,dried and evaporated to give2-methyl-2-(B-carbomethoxyethyl)cyclopentane-'1,3-dione which waspurified by distillation.

(VII) The above prepared diketoester is then hydrolyzed to the acid bytreatment with 1% potassium carbonate in warm methanohwater (1:1) foreight hours. A total of 5 g. of this acid is mixed with 50 ml. of aceticanhydride containing 2 g. of anhydrous sodium acetate and the mixtureboiled for five hours. The acetic anhydride is then removed bydistillation in vacuo to furnish a residue which is poured into waterand extracted with ethyl acetate. The ethyl acetate extracts arecombined, washed neutral with water, dried and evaporated. Purificationof the resulting residue by vacuum distillation affords 1.2 g. of theenol lactone (VII"):

0 OH: I

N v1r" tography on alumina to furnish 1.3 g. of the following alcohol:

O H CH: I

which is converted into the corresponding benzoate by treatment withbenzoyl chloride in pyridine. The methyl ester is hydrolyzed to the acidwhich is then cyclized by the procedure described above to furnish theenol lactone of Formula VII (R is methyl; Ac is benzoyl).

By using 2-ethylcyclopentane-1,3-dione and2-propylcyclopentane-1,3-dione in place of 2-methylcyclopentane-1,3-dione in the above procedure, the corresponding enol lactoneswherein R is ethyl and propyl, respectively, are obtained.

EXAMPLE 4 The process of Example 3 is repeated with the exception ofusing an equivalent amount of the phosphonate of Formula IX (R is ethyl;R is hydrogen; R and R are methyl and Ac is benzoyl) in place ofdimethyl methylphosphonate and the substituted bicarbocyclic ketone (X)(R is hydrogen; R and R are methyl and Ac is benzoyl) is obtained.

In the above formulas, Ac, R and R are as defined hereinabove, R ishydrogen or a lower alkoxy of 1 to 6 carbon atoms and R is a lower alkylof 1 to 6 carbon atoms.

By using other phosphonates of Formula IX in the above process, thecorrespondingly substituted vz,fl-unsaturated bicarbocyclic ketone ofFormula X is obtained.

The phosphonates of Formula IX can be obtained by using an equivalentamount of the bromide (XI) in place of the ethylene ketal of1-bromopentan-4-one in the procedure set out in Example 2. The bromide(XI) can be prepared from the corresponding acid by the followingprocedure.

Ten grams of m-methoxycinnamic acid in 100 ml. of ethanol ishydrogenated with 0.5 g. of pre-reduced 10% palladium-on-charcoal untilthe uptake of hydrogen ceases. The catalyst is removed by filtration andthe filtrate evaporated to yield 3-(m-methoxyphenyl)propionic acid.

A solution of 5 g. of the foregoing propionic acid in 100 ml. oftetrahydrofuran is added cautiously to a boiling solution of 250 ml. oftetrahydrofuran containing 3 g. of lithium aluminum'hydride. Thereaction mixture is refluxed overnight with stirring and then cooled andthe excess of hydride decomposed by the cautious addition of ethylacetate and then saturated sodium sulfate. The resulting clear solutionis decanted and dried over sodium sulfate. The solvent remaining isremoved by distillation to give 3-(m-methoxyphenyl)propanol which ispurified by distillation in vacuo. One gram of this propyl alcohol in50. ml. of benzene is boiled with a slight excess of phosphoruspentabromide until thin layer chromatography no longer indicates thepresence of starting alcohol. The reaction mixture is cooled, washedwith water and dilute sodium carbonate solution, dried over sodiumsulfate and concentrated to dryness to give 3-(m-methoxyphenyl)pro- 4 8pionyl bromide (XI) (R is hydrogen; R is methyl) which is purified bydistillation.

By using 3,5-dimethoxycinnamic acid in place of m-methoxycinnamic acid,th'e bromide (XI) in which R is methoxy and R is methyl is obtained.

The bicarbocyclic ketones of Formula X above can be converted into estra1,3,5(l0),8,14 pentaenes by treatment with p-toluenesulfonic acid inbenzene or by the method of 11.5. Pat. 3,317,566. The thus-obtainedestra- 1,3,5 10),8,14-pentaene can be converted into therapeuticallyuseful steroids by known procedures, see for example, U.S. Pat.3,337,542.

EXAMPLE 5 To a suspension of 4 g. of dibutyl methylphosphonate in ml. ofdry monoglyme at about -78 under nitrogen, there is added with stirringone equivalent of n-butyl lithium in hexane. After about 10 minutes,there is added one equivalent of 17,8-acetoxy-4oxa-androst-S-en-3-one in75 ml. of dry tetrahydrofuran while maintaining the temperature at about-78". The reaction mixture is allowed to warm to room temperature andthen left to stand for about four hours. The reaction mixture is dilutedwith water and extracted with ether. The ether extracts are combined,washed, dried and evaporated to give the testosterone acetate.(17B-acetoxyandrost-4-en-3-one) which can be purified by chromatography.

By using diethyl ehtylphosphonate in the process of this example, thecorrespondingly substituted tetracarbocyclic compound is obtained, i.e.4-methyl testosterone acetate.

By using other steroidal enol lactones in the above process in place of17fi-acetoxy-4-oxa-androst-5-en-3-one as the starting material, e.g.4-oxa-cholest-5-en-3-one, 3- ethoxy-17-oxa-D-homoestra 1,3,5(10),15tetraen-17- one, 17,20;20,2l bismethylenedioxy-llp-hydroxypregn-5-en-3-one, and the like, the corresponding c p-unsaturatedtetracarbocyclic ketone is obtained, e.g. cholest-4- en-3-one, 3ethoxy-D-homoestra-l,3,5(10),14-pentaen l7-one, and17,20;20,2l-bismethylenedioxy-lI/S-hydroxypregn-4-en-3-one.

EXAMPLE 6 omfio out-go (x111) xrv To a suspension of 2 g. of dibenzoylmethylphosphonate in 30 ml. of dry tetrahydrofuran cooled to atemperature of about -60 under nitrogen, there is added 1.1 equivalentsof phenyl lithium in hexane with stirring. After about five minutes,there is added, while maintaining the temperature at about -60, 0.95equivalents of angelica lactone (XIII) in 40 ml. of dry tetrahydrofuran.The reaction mixture is allowed to warm to room temperature and thenleft to stand for about two hours. The mixture is then diluted withwater and the product extracted with ether to give3-methylcyclopent-2-en-l-one (XIV) which can be purified by vacuumdistillation.

By using a mono-substituted methylphosphonate, for example, diethylethylphosphonate in the above process,

the corresponding Z-substituted a,/3-unsaturated cyclopentone isobtained, e.g. 2,3-dimethylcyclopent-2-en-l-one.

EXAMPLE 7 To a solution of 5 g. of dimethyl methylphosphonate in 100 ml.of dry tetrahydrofuran cooled to about 78 under nitrogen, there is addedwith stirring one equivalent of n-butyl lithium in hexane. After about10 minutes, there is added one molar equivalent of3-methoxy-16-oxaestra-1,3,5(10),8,14-pentaen-17-one in drytetrahydrofuran while maintaining the temperature at about -78. Themixture is allowed to warm to room temperature and then left to stand atroom temperature for five hours. The mixure is diluted with water andthen extracted with ether. The ether extracts are combined andconcentrated to furnish a residue which is chromatographed on neutralalumina eluting with benzene to afford 3-methoxy-14B-estra-1,3,5(10),8,15-pentaen-17-one and3-methoxy-14aestra1,3,5(10),8,l5-pentaen-7-one which can be furtherpurified by recrystallization from aqueous methanol.

0.5 g. of 3-methoxy-l4a-estra-1,3,5(10),8,15-pentaen- 17-one in 25 ml.of ethanol is reduced catalytically with 50 mg. of 5%palladium-on-charcoal until a molar equivalent of hydrogen is taken up.The catalyst is filtered ofi and the filtrate evaporated to dryness toyield the known 3-methoxyestra-1,3,5(l0),8-tetraen-17-onc which can beconverted into estrone methyl ether by procedures outlined in Chemistry& Industry (London), 1022 (1960) or into 19-nor-A -steroids using theprocedure of, for example, US. Pat. 3,318,922.

By repeating the above process using other 16-oxa steroids of theFormula XV, e.g. 3-methoxy-15-methyl- 16-oxa-estra-1,3,5(10),6,8,14-hexaen-17-one as the tetracyclic enol lactone startingmaterial, the corresponding steroidal ketone (tetracarbocyclic ketone)of the Formula XVI is obtained, e.g. 3-methoxy-15-methyl-14a-estra-L3,5(10),6,8,15-hexaen-l7-one and 3-methoxy l5 methyll4fi-estra-1,3,510),6,8,15-hexaen-l7-one.

o R4 K R2 EXAMPLE 8 The process of Example 2 is repeated with theexception that the phosphonate employed is a phosphonate of Formula XVIIand there is obtained the substituted tricarbocyclic ketone (XVIII)which is useful in the synthesis of valuable 2-methyl-19-nor steroidsand Z-methylandrostene steroids using the procedure of, for example,Velluz et al., ibid.

0 Ac R4 (XVIII) The mono-substituted methylphosphonates of Formula XVIIcan be prepared by the procedure described in Example 2 using theethylene ketal of l-bromo-B-methylpentan-4-one as the starting material.This bromide starting material can be prepared according to thefollowing procedure.

A mixture of 0.5 mole of l-acetoxypentan-4-one and 0.5 mole ofpiperidine in benzene is refluxed using a water separator until no more'water distills from the reaction mixture. The reaction mixture is thencooled, washed and dried to afford the 4-piperidyl-l-acetoxypent- 3-ene(XIX). A mixture of 5 g. of XIX in m1. of dioxane is treated with anexcess of methyl iodide at 20 C. for 18 hours and then heated at 70 C.for six hours. The reaction mixture is concentrated to a small volume,diluted with water and 1-acet0xy-3-methylpentan-4-one isolated byextraction with ethyl acetate. A mixture of 0.5 g. of this ketone, 100mg. of p-toluenesulfonic acid, 3 ml. of ethyleneglycol and 100 ml. ofbenzene is refluxed using a water separator for 24 hours. The reactionmixture is cooled and then 100 ml. of ethanol and 2 g. of potassiumhydroxide are added. This mixture is refluxed for six hours, cooled,diluted with water and the corresponding ethylene ketal is isolated byextraction with ethyl acetate. A solution of 0.1 mole of the ketal in 50ml. of dimethylformamide containing 0.1 mole of triphenylphosphine isreacted with 0.1 mole of carbon tetrabromide at room temperature for 18hours. The mixture is diluted with water and extracted with ether. Theether extracts are combined, washed with water, dried and evaporated.The residue is chromatographed on 400 g. of alumina eluting withhexane-benzene and benzene to give the ethylene ketal of1-bromo-3-methylpentan-4-one.

EXAMPLE 9 A mixture of 10 g. of l-chloropentan-4-one, 100 ml. of etherand 1 g. of lithium aluminum hydride is allowed to stand at 20 C. for 20hours. The reaction mixture is diluted with water and separated. Theorganic phase is washed with water, dried and evaporated to givel-chloropentan-4-ol which is purified by distillation. Two ml. ofdihydropyran is added to a solution of 1 g. of l-chloropentan-4-ol in 15ml. of benzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonic acid is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays and is then washed with aqueous sodium carbonate solution andwater, dried and evaporated to yield 4-(tetrahydropyran-2'-yloxy)-l-chloropentane which is subjected to theprocedure described in Example 2 to give the phosphonate (XX).

The process of Example 2 is repeated with the exception that thephosphonate of Formula XX (R is ethyl) is used in place of thephosphonate (V) (R is ethyl) and there is obtained the tricarbocyclicketone (XXI) which can be converted into l9-nor steroids describedhereinabove, see for example, Example 2.

OAc

OH: a?

CH; (XXI) EXAMPLE 10 To a suspension of 4 g. of diethyl(4-chloropentyl-3- enyl)phosphonate in 50 m1. of dry monoglyme at about78, there is added 1.1 equivalents of butyl lithium in hexane withstirring under nitrogen. After about 10 minutes, there is added 1.1equivalents of the tricyclic enol lactone (I) (R is methyl; Ac isbenzoyl) in 60 ml. of dry monoglyme while maintaining the temperature atabout -78. The reaction mixture is allowed to warm to room temperatureand then left to stand at room temperature for about two hours. Thereaction mixture is diluted with water and then extracted with ether.The ether extracts are combined, washed, dried over magnesium sulfateand evaporated under reduced pressure to afford the 11,13- unsaturatedtricarbocyclic ketone (XXII) (R is methyl; Ac is benzoyl) which can bepurified further by chromatography on alumina.

CH: of a' 0 GH, (XXII) The tricarbocyclic ketone (XXII) is a usefulintermediate for the synthesis of valuable 19-nor steroids using knownprocedures such as described in US. Pat. 3,050,- 550, 3,019,252 and3,150,152.

The phosphate used in the process of this example can be preparedaccording to the following procedure.

A mixture of 10 g. of 1-bromopentan-4-one, 100 ml. of carbontetrachloride and g. of phosphorus pentachloride is refluxed for hours.The reaction mixture is then cooled, washed with dilute sodium carbonateand water, dried over magnesium sulfate and evaporated to give1-bromo-4-chloropent-3-ene which is purified by distillation andconverted into the phosphonate by the procedure described in Example 2.

EXAMPLE 11 To a suspension of 4 g. of diethyl4,4-dimethoxybutylphosphonate in 50 ml. of dry monoglyme at about 70under nitrogen, there is added one equivalent of phenyl lithium inhexane with stirring. After about five minutes, there is added 1.0equivalent of the bicyclic enol lactone (VII) (R is ethyl; Ac isbenzoyl)) in 50 ml. of dry monoglyme while maintaining the temperatureat about 70. The reaction mixture is allowed to warm to room temperatureand then allowed to stand at room temperature for 3.5 hours. Thereaction mixture is then diluted with water and extracted with ether.The ether extracts are combined, washed, dried over magnesium sulfateand evaporated under reduced pressure. The residue is chromatographed onsilica gel to afford the 0:,[3-11I1S3tl113t6d bicarbocyclic ketone(XXIII) (R is ethyl; Ac is benzoyl).

A mixture of l g. of the above bicarbocyclic ketone, 25 ml. of dioxaneand 1 ml. of 5% aqueous HCl is boiled 15 minutes. The reaction mixtureis allowed to cool, poured into water and the resulting mixtureseparated. The organic phase is evaporated to dryness to furnish thecorresponding aldehyde which is taken up in 20 ml. of acetone, cooled to0 C. and a slight molar excess of Jones reagent (prepared by mixing 26g. of chromium trioxide with 23 ml. of concentrated sulfuric acid anddiluting with water to ml.). Upon completion of the oxidation asfollowed by thin layer chromatography, the reaction mixture is dilutedwith water and then extracted with ethyl acetate. The ethyl acetateextracts are combined, washed with water, dried and evaporated underreduced pressure to afford the acid (XXIV) (R is ethyl; Ac is benzoyl)which is a valuable intermediate for the synthesis of known l9-nor-A andM -steroids useful as therapeutic agents using the procedure of, forexample, Belgium Pat. 629,251 (1963); French Pat. 1,465,400 (1965) orVelluz et al., ibid.

Cl g (XXIII) The diethyl 4,4-dimethoxybutylphosphonate employed in thisexample can be obtained according to the following procedure.

To 0.5 mole of diethylmalonate in 0.5 liter of dry benzene is added 0.5mole of sodium hydride cautiously and the mixture stirred until hydrogenevolution ceases. Then 0.5 mole of bromoacetaldehydedimethylacetal [(CHO) -CHCH Br] in 100 ml. of benzene is added and the mixture stirredovernight followed by refiuxing for two hours. The reaction mixture iscooled, washed with water and purified by vacuum distillation to give18,5-dimethoxyethylmalonic acid diethyl ester. A mixture of 5 g. of thisester in 100 ml. of ethanol containing 5 g. of sodium hydroxide isheated under reflux until evolution of carbon dioxide ceases. Thereaction mixture is then saturated with carbon dioxide and evaporated todryness under vacuum. The residue is suspended in 50 ml. of drydimethylformamide to which is added a large excess of methyl iodide. Thereaction mixture is stirred at room temperature for about 24 hours andthen poured into water. The resulting mixture is extracted with etherand the ether extracts combined, washed with water and evaporated togive 4,4dimethoxybutyric acid methyl ester which is purified bydistillation. A mixture of 4 g. of this methyl ester, 50 ml. of drytetrahydrofuran and 1.1 equivalents of lithium aluminum hydride isrefluxed overnight. The reaction mixture is allowed to cool and thenfiltered with water. This mixture is extracted with ether and the etherextracts are combined, washed, dried and evaporated to dryness to afford4,4-dimethoxybutanol A solution of 0.1 moles of 4,4-dimethoxybutanol in50 ml. of dimethylformamide containing 0.1 mole of triphenylphosphine isallowed to react for 18 hours with 0.1 mole of carbon tetrabromide. Themixture is diluted with water and extracted with ether. The etherextracts are combined, washed with water, dried and evaporated to acrude product which is purified by distillation to yield,4,4-dimethoxybutylbromide. This bromide is then converted into thediethyl phosphonate using the procedure described in Example 2.

EXAMPLE 12 The process of Example 11 is repeated using a phosphonate(XXV) as the phosphonate reagent and n-butyl lithium as the base and thecorresponding carbocyclic ketone (XXVI) is obtained which can beconverted into valuable 6-methyl steroids.

(HuCNh- CHa (XXVI) 0:0 H 0% efi AH.

(XXVIII) (H5020 )gCH H CH (H;

(XXVII) EXAMPLE 13 Diethyl methylphosphonate (1.94 g.) suspended in 50ml. of dry tetrahydrofuran is treated with 1.1 equivalents of butyllithium in hexane under nitrogen at about -78.

After 10 minutes, one equivalent of benzalphthalide in 1 0 ml. oftetrahydrofuran is added while maintaining the temperature at about 78.The reaction mixture is allowed to warm to room temperature and thenleft to stand at room temperature for three hours. The reaction mixtureis diluted with water and then extracted with ether. The ether extractsare combined, washed with water, dried and the solvent removed undervacuum. The residue is chromatographed on silica eluting with methylenechloridezhexane (4:1) to afiord 3-benzylind-2-end-lone and a smallamount of starting material.

EXAMPLE 14.

The process of Example 3 is repeated with the exception that thephosphonate (XXX) (R is ethyl) is used in place of dimethylmethylphosphonate and there is obtained the substituted bicarbocyclicketone (XXXI) (R is methyl; Ac is benzoyl).

The novel bicarbocyclic ketone (XXXI) is useful for the preparation ofthe known tricarbocyclic ketones (XXII) which can be used to prepare19-nor steroids. Thus, hydrogenation of the bicarbocyclic ketone using,for example, 5% palladium-on-charcoal in ethanol followed bydeketalization under mild condition such as 1% sulfuric acid in dioxanewith refluxing for one hour furnishes the intermediate (XXXIH) which canbe cyclized using, e.g. a base as described by, e.g. Velluz et al.,ibid., U.S. Pats. 3,102,145 and 3,150,152, or French Pat. 1,480,- 247,to furnish the tricarbocyclic ketone XXII (Ac is hydrogen).

(XXXII) The phosphonate (XXX) can be prepared using the followingprocedure.

A mixture of 0.5 moles of 1,3-dithiane and 300 ml. of tetrahydrofurancooled to 30 is treated with 0.5 molar equivalents of 1.5 molar n-butyllithium in hexane under nitrogen and stirred for 15 hours at 20. Then0.5 moles of the tetrahydropyranyl ether of 3-bromopropanol in 200 m1.of tetrahydrofuran is added slowly with stirring at -5 and then left for14 hours at 0 under nitrogen. The resulting mixture is cooled to -30 andtreated with an additional 0.5 molar equivalent of 1.5 molar n-butyllithium in hexane. After 1.5 hours, 0.5 moles of4-chlorol-bromopent-B-ene in 200 ml. of tetrahydrofuran is added. Thereaction mixture is left standing for 18 hours at 0 1 5 and then allowedto warm to room temperature for four hours. Water is added and theresulting mixture extracted with ether. The ether extracts are combined,Washed with water, dried and concentrated. The resulting dialkylatedthiane (XXXIII) is dissolved in methanol and stirred for two hours with20 ml. of 1% oxalic acid solution. The

reaction mixture is poured into water containing an excess of sodiumcarbonate solution and then extracted with ether to afford thecorresponding free hydroxy compound. The free hydroxy compound isdissolved in dry ethylene glycol containing 0.5 g. of mercuric chloride.This reaction mixture is allowed to stand overnight and then heated to60 for five hours. After cooling, water is added and the ketal (XXXIV)isolated by extraction with ether. A mixture of 2 g. of the ketal and 30ml. of methylene chloride: pyridine (2:1) is cooled to -70 and thentreated with one equivalent of tosylchloride in methylene chloride. Themixture is left standing at 0 for 18 hours and then allowed to warm toroom temperature. The mixture is then diluted with water and theresulting tosylate isolated by extraction with methylene chloride andpurified by chromatography on deactivated alumina. This tosylate (0.5g.) in 25 ml. of acetone is refluxed for 24 hours with 0.5 g. of sodiumiodide. After cooling, the reaction mixture is diluted with water andextracted with ether. The resulting crude iodide is treated with sodiumhydride and diethyl phosphite as described in Example 2 to furnish thephosphonate (XXX) (R is ethyl).

Alternatively, the tosylate can be reacted with sodium hydride anddiethyl phosphite using the procedure of Example 2 to obtain thephosphonate.

By repeating the preparation using other phosphites, e.g. dibutylphosphite, dicyclohexyl phosphite, dimethyl phosphite or diphenylphosphite in place of diethyl phosphite, the corresponding phosphonatesare obtained.

The process of Example 2 is repeated using as the phosphonate reagent,the phosphonate of Formula XXXV (R is ethyl) and there is obtained thetricarbocyclic ketone (XXXVI) (Ac is 'benzoyl) which can be convertedinto 19-nor steroids or androstane steroids by methods disclosed in theJournal of American Chemical Society, 82, #21, 5464 (1967).

(XXXV) 1 6 The phosphonate (XXXV) can be obtained according to thefollowing outlined procedure.

(30,011, com ('30 CHQN: airmen. (Maw-CH: on; cn.

l L N N 1 (2 (3) COZCH-(CHZ)5CH:

CH:CH:OH CH1 om CHafi-iifi: CH: CH;

l ON N carom-B r clam-0H. --N

(XXXV) Ten grams of the isoxazole (1) is heated at reflux with 200 ml.of 1% sodium hydroxide in methanol for five hours. The reaction mixtureis then acidified to pH 3 with HCl and the acidified mixture is thenconcentrated to a small volume under reduced pressure. Water is addedand the acid isolated by extraction with ethyl acetate. The crude acid(9 g.) is taken up in methanol and treated with one equivalent of sodiummethoxide. The alcohol is evaporated and the residue dried under reducedpressure. The residue is then suspended in dry benzene and treated at 0C. with the excess of oxalyl chloride. After the evolution of gasceases, the reaction mixture is allowed to warm to room temperature andthe excess of oxalyl chloride removed by evaporation of the solventmedium to dryness. The resulting acid chloride (2) is taken up inbenzene and treated with an excess of ethereal diazomethane. After theformation of the diazoketone is complete, the ether is removed and theresulting diazoketone heated under reflux in octane-2- 01 until nitrogenevolution ceases. The crude product is purified by distillation andreduced with an excess of lithium aluminum hydride in 200 m1. oftetrahydrofuran under reflux. The reaction mixture is decomposed bycautious addition of ethyl acetate and the inorganic salts precipitatedby the addition of concentrated sodium sulfate solution. The solution isthen filtered and evaporated to yield the alcohol (5) which is purifiedby distillation. The alcohol (5) is then treated with phosphorustribromide in benzene to give the bromide (6) which is converted intothe phosphonate (XXXV) by the procedure described in Example 2.

EXAMPLE 16 :l (O R): 0 R 0 -CH;- H

H; R 0 CH:CHCH3 (XXXVII) (XXXVIII) The process of Example 3 is repeatedwith the exception that dimethyl methylphosphonate is replaced with anequivalent amount of the phosphonate (XXXVII) (R is ethyl; R ishydrogen; -R is methyl) and the corresponding substituteda,fi-unsaturated bicarbocyclic ketone (XXXVHI) is obtained.

The bicarbocyclic ketones of Formula XXXVIII are excellent intermediatesfor the production of valuable 7- methyl steroids using the proceduresdescribed in Example 4.

The phosphonates of Formula XXXVII can be prepared according to thefollowing outlined procedure wherein R R and X are as definedhereinabove.

OHiX I CHiOH 18. CH;- H R CH H Ha H: 0)

(XXXVII) A solution of 0.6 mole of the aldehyde (7) and 0.5 mole ofmethyl a-bromopropionate in 80 ml. of dry benzene is added dropwise to0.6 mole of zinc dust. After 15 ml. of the solution is added, themixture is heated to initiate the reaction. The remaining portion of thesolution is then added during one hour. The resulting mixture is cooled,washed with water, dried and then refluxed with 0.2 g. ofp-toluenesulfonic acid for five hours. After cooling, the reactionmixture is washed with dilute sodium bicarbonate solution and water andthen dried and purifiedby distillation to give 8. One gram of 8 in 25ml. of ethanol is hydrogenated with 0.1 g. of palladium/ carbon catalystuntil 1 molar equivalent of gas is taken up. The catalyst is filtered 0Eand solvent evaporated to give 2-methyl 3 (substituted phenyl)propionicacid methyl ester. One gram of this ester in 100 ml. of tetrahydrofuranis reduced with 2 g. of lithium aluminum hydride until thin layerchromatography indicates the absence of starting ester. The reactionmixture is cooled, treated cautiously with an excess of ethyl acetatefollowed by saturated sodium sulfate solution. The organic layer isdecanted ofi, dried with sodium sulfate and evaporated to give thealcohol (9) 'which is converted into the corresponding halide ortosylate (10) by procedures described herein (see Examples 4, 8 and 14).The halide or tosylate (10) is then converted into the phosphonate(XXXVII) using the procedure described in Example 2.

hydrolysis conventionally used to remove a tetrahydropyranyl protectinggroup, e.g. dilute hydrochloric acid at room temperature, thecorresponding free alcohol (XXI) is obtained which can be subjected tooxidation using, for example, chromium trioxide in pyridine at roomtemperature to give the corresponding carbonyl (XXI"). Thetricarbocyclic (XXI") can be converted into valuable estrogens usingknown procedures, see U.S. Pat. 3,150,152.

CH7 elf (XXI') (XXI) 0 R -CH IQ (O R):

wherein,

R is phenyl benzyl, alkyl having from 1 to 8 carbons,

cyclohexyl, methoxyethyl or ethoxyethyl, and

R is a member selected from the groups:

2. A phosphonate of claim 1 wherein R is lower alkyl.

3. A phosphonate of claim 1 wherein R is phenyl.

4. A phosphonate of claim 1 wherein R is ethyl and R is UNITED STATESPATENTS 3,413,311 11/1968 Cross 260340.9 X

ALEX MAZEL, Primary Examiner I. H. TURNIPSEED, Assistant Examiner U.S.C1. X.R.

260-2943 A, 307 R, 327 M, 343.2 R, 345.9, 343.6, 397.3, 473 R, 476 C,488 R, 514 R, 586 R, 586 H, 612 R, 612 D, 950, 951, 956, 961

Page 1 of 2 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION PATENT NO. 3, 773, 789

DATED November 20 1973 INVENTOR(S) JOHN H. FRIED It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 5, line 58, "5 g. should read 5.5 g.

Column 6, lines 67-78, that portion of formula (VII") k II hould read lO Column 13, lines 27-30 that portion of formula (XXVI) Column 14, lines57-60, that portion of formula (XXXII) I r I I should read C H shouldread =0 CH c g 2 cPf 2 Column 17, line 17, that portion of formula (7)should read R D-k Page 2 of 2 UNITED STATES PATENT AND TRADEMARK OFFICECERTIFICATE OF CORRECTION PATENT NO. 3, 773,789 DATED November 20, 1973VENT0R 5 JOHN H. FRIED It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 18, line 14, that portion of formula (XXI") O=CH should read O=CSigned and Scaled this Eighteenth 0f January 1977 [SEAL] Arrest:

RUTH C. MASON Arresting Officer

